Somatic Alterations Impact AR Transcriptional Activity and Efficacy of AR-Targeting Therapies in Prostate Cancer

SIMPLE SUMMARY: For patients whose prostate cancer spreads beyond the confines of the prostate, treatment options continue to increase. However, we are missing the information that is needed to choose for each patient the best treatment at each step of his cancer progression so we can ensure that maximal remissions and prolonged survival are achieved. In this review, we examine whether a better understanding of how the activity of the target for the default first treatment, the androgen receptor, is regulated in prostate cancer tissues can improve prostate cancer treatment plans. We consider the evidence for variability of androgen receptor activity among patients and examine the molecular basis for this variable action. We summarize clinical evidence supporting that information on a prostate cancer’s genomic composition may inform on its level of androgen receptor action, which may facilitate choice for the most effective first-line therapy and ultimately improve prostate cancer treatment plans overall. ABSTRACT: Inhibiting the activity of the ligand-activated transcription factor androgen receptor (AR) is the default first-line treatment for metastatic prostate cancer (CaP). Androgen deprivation therapy (ADT) induces remissions, however, their duration varies widely among patients. The reason for this heterogeneity is not known. A better understanding of its molecular basis may improve treatment plans and patient survival. AR’s transcriptional activity is regulated in a context-dependent manner and relies on an interplay between its associated transcriptional regulators, DNA recognition motifs, and ligands. Alterations in one or more of these factors induce shifts in the AR cistrome and transcriptional output. Significant variability in AR activity is seen in both castration-sensitive (CS) and castration-resistant CaP (CRPC). Several AR transcriptional regulators undergo somatic alterations that impact their function in clinical CaPs. Some alterations occur in a significant fraction of cases, resulting in CaP subtypes, while others affect only a few percent of CaPs. Evidence is emerging that these alterations may impact the response to CaP treatments such as ADT, radiation therapy, and chemotherapy. Here, we review the contribution of recurring somatic alterations on AR cistrome and transcriptional output and the efficacy of CaP treatments and explore strategies to use these insights to improve treatment plans and outcomes for CaP patients.